The biochemistry and physiology of the renin-angiotensin system will be examined in vitro and in vivo in experimental animals and in man in relation to circulatory homeostasis. The program will focus on two major areas: the action and regulation of angiotensin I (AI) converting enzyme in vivo and in vitro and the regulation of angiotensin II (AII) metabolism in vivo. In pursuit of the former goal, we will perform detailed studies of the mechanism of action of converting enzyme and of possible disorders of and physiologic regulatory mechanisms for converting enzyme in man and in animal models. The latter will include acute and chronic hypoxia and alterations in sodium intake and posture. We will attempt to produce animal models of converting enzyme insufficiency by inducing oxygen toxicity in the rat lung and by injecting histamine depleting substances into the pulmonary circulation of the rat. Simultaneous measurements of pulmonary and plasma converting enzyme activity will be made in order to make a quantitative assessment of the contribution of the lung to the pool of circulating converting enzyme. We will search for evidence of angiotensin conversion in the brush border of the proximal tubule in order to elucidate the problem of the intrarenal origin of angiotensin II. Studies of angiotensin II metabolism, including sites, enzymatic mechanisms and functional roles of metabolites, will be performed. To achieve this goal we will investigate the regulation of AI conversion and AIII metabolism in the kidney of dogs which have been maintained on diets of high or low sodium intake, which are expected to produce chronic alterations in renal hemodynamics and possible in renal angiotensinase activity. Further, we will examine the hypothesis that the kidney distal to a stenosed renal artery has a diminished ability to remove AII from the circulation.